Pancreatic cancer is the fifth leading cause of cancer death in this country and it is almost uniformly fatal. The poor survival can be attributed to the lack of early detection and effective treatments. Efforts to improve these two aspects have been hampered by the absence of a good animal model of pancreatic cancer. A reliable mouse model is urgently needed. Tremendous progress has been made in understanding the molecular genetics of human pancreatic adenocarcinoma within the last decade. It is now clear that pancreatic cancer is a genetic disease and the tumor suppressor genes most frequently inactivated include p16INK4a and DPC4. This valuable information can be utilized to create mouse models that directly mirror human pancreatic adenocarcinoma. The main objective of this pilot project is to create a mouse model of ductal pancreatic adenocarcinoma. The first aim is to conditionally delete a tumor suppressor gene, DPC4, in selective tissues of the mouse. DPC4 is not only an important tumor suppressor gene in pancreatic tumorigenesis, it is required for endoderm differentiation during embryogenesis. Conditional deletion of DPC4 will hopefully bypass this developmental requirement and allow the inactivation of DPC4 to affect only tumorigenesis. Additional mutations may be required for tumor development in the conditionally deleted DPC4 mouse. The second aim of the project will therefore explore the effects of P16INK4a inactivation in the conditionally deleted DPC4 background. P16INK4a is another important tumor suppressor gene inactivated in almost 100 percent of human pancreatic adenocarcinoma and its inactivation occurs earlier than DPC4 mutation in human pancreatic tumorigenesis. The compound mutant mouse may exhibit more aggressive tumor phenotypes and demonstrate the importance of sequential mutation in tumorigenesis. Once developed, a mouse model of pancreatic adenocarcinoma will serve as an invaluable tool for the development and testing of new treatments and new methods for the early detection of pancreatic cancer.